View source for PIAS3

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox_gene}}
'''E3 SUMO-protein ligase PIAS3''' is an [[enzyme]] that in humans is encoded by the PIAS3 [[gene]].<ref name="Ueki_1999">{{cite journal | vauthors = Ueki N, Seki N, Yano K, Saito T, Masuho Y, Muramatsu M | title = Isolation and chromosomal assignment of a human gene encoding protein inhibitor of activated STAT3 (PIAS3) | journal = Journal of Human Genetics | volume = 44 | issue = 3 | pages = 193–196 | date = June 1999 | pmid = 10319586 | doi = 10.1007/s100380050141 | s2cid = 12454718 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PIAS3 protein inhibitor of activated STAT, 3 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10401 }}</ref>

== Discovery ==

IAS proteins were originally identified in studies that were aimed to decipher the Janus Kinase (JAK)/STAT signaling pathway.  Originally, PIAS3 was found to interact specifically with phosphorylated STAT3 in Interleukin -6 (IL-6) activated murine myeloblast M1 cells.<ref>{{cite journal | vauthors = Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K | title = Specific inhibition of Stat3 signal transduction by PIAS3 | journal = Science | location = New York, N.Y. | volume = 278 | issue = 5344 | pages = 1803–1805 | date = Dec 1997 | pmid = 9388184 | doi = 10.1126/science.278.5344.1803 | bibcode = 1997Sci...278.1803C }}</ref> This interaction is mediated via PIAS3 binding to the STAT3 DNA binding domain. Hence, STAT3 transcriptional activity is inhibited by the physical prevention of its binding to target genes. Subsequently, PIAS3 was also found to be a regulator protein of other key transcription factors, including [[MITF]],<ref name="Levy_2002">{{cite journal | vauthors = Levy C, Nechushtan H, Razin E | title = A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor | journal = The Journal of Biological Chemistry | volume = 277 | issue = 3 | pages = 1962–1966 | date = Jan 2002 | pmid = 11709556 | doi = 10.1074/jbc.m109236200 | s2cid = 25141003 | doi-access = free }}</ref> [[NFκB]],<ref name="Jang_2004">{{cite journal | vauthors = Jang HD, Yoon K, Shin YJ, Kim J, Lee SY | title = PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit | journal = The Journal of Biological Chemistry | volume = 279 | issue = 23 | pages = 24873–24880 | date = Jun 2004 | pmid = 15140884 | doi = 10.1074/jbc.m313018200 | s2cid = 20036187 | doi-access = free }}</ref> [[SMAD (protein)|SMAD]]<ref name="Bava_2004">{{cite journal | vauthors = Bava KA, Gromiha MM, Uedaira H, Kitajima K, Sarai A | title = ProTherm, version 4.0: thermodynamic database for proteins and mutants | journal = Nucleic Acids Research | volume = 32 | issue = Database issue | pages = D120–D121 | date = Jan 2004 | pmid = 14681373 | pmc = 308816 | doi = 10.1093/nar/gkh082 }}</ref> and estrogen receptor.<ref name="Sentis_2005">{{cite journal | vauthors = Sentis S, Le Romancer M, Bianchin C, Rostan MC, Corbo L | title = Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity | journal = Molecular Endocrinology | location = Baltimore, Md. | volume = 19 | issue = 11 | pages = 2671–2684 | date = Nov 2005 | pmid = 15961505 | doi = 10.1210/me.2005-0042 | doi-access = free }}</ref>

== PIAS family ==

The mammalian [[Protein inhibitor of activated STAT|PIAS family]] consists of four members: [[PIAS1]], [[PIAS2]], PIAS3 (this gene) and [[PIAS4]]. In ''[[Drosophila]]'', a single PIAS homologue named dPIAS/Zimp has been identified.<ref>{{cite journal | vauthors = Mohr SE, Boswell RE | title = Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster | journal = Gene | volume = 229 | issue = 1–2 | pages = 109–116 | date = Mar 1999 | pmid = 10095110 | doi = 10.1016/s0378-1119(99)00033-5 }}</ref> In yeast, two  PIAS-related proteins were identified namely SIZ1 and SIZ2.<ref>{{cite journal | vauthors = Islam HK, Fujioka Y, Tomidokoro T, Sugiura H, Takahashi T, Kondo S, Katoh H | title = Immunohistochemical study of genetic alterations in intraductal and invasive ductal tumors of the pancreas | journal = Hepato-gastroenterology | volume = 48 | issue = 39 | pages = 879–883 | year = 2001 | pmid = 11462947 }}</ref>  The PIAS family contains more than 60 proteins, most of them [[transcription factor]]s that can be either positively or negatively regulated through multiple mechanisms.

== Structure ==

The SAF-A/B, Acinus and PIAS (SAP) domain is located at the N-terminal of PIAS proteins.<ref>{{cite journal | vauthors = Shuai K | title = Regulation of cytokine signaling pathways by PIAS proteins | journal = Cell Research | volume = 16 | issue = 2 | pages = 196–202 | date = Feb 2006 | pmid = 16474434 | doi = 10.1038/sj.cr.7310027 | s2cid = 755228 | doi-access = free }}</ref> This evolutionarily conserved domain is found in proteins ranging from yeast to human and is shared by other chromatin-binding proteins, such as scaffold attachment factor A and B.<ref name="Aravind_2000">{{cite journal | vauthors = Aravind L, Koonin EV | title = SAP - a putative DNA-binding motif involved in chromosomal organization | journal = Trends in Biochemical Sciences | volume = 25 | issue = 3 | pages = 112–114 | date = Mar 2000 | pmid = 10694879 | doi = 10.1016/s0968-0004(99)01537-6 }}</ref> The SAP domain can recognize and bind to AT-rich DNA sequences present in scaffold-attachment regions/matrix-attachment regions.<ref>{{cite journal | vauthors = Kipp M, Gohring F, Ostendorp T, Drunen CM, Driel R, Przybylski M, Fackelmayer FO | title = SAF-Box, a conserved protein domain that specifically recognizes scaffold attachment region DNA | journal = Molecular and Cellular Biology | volume = 20 | issue = 20 | pages = 7480–7489 | date = Oct 2000 | pmid = 11003645 | pmc = 86301 | doi = 10.1128/mcb.20.20.7480-7489.2000 }}</ref> These elements are frequently found near gene enhancers and interact with nuclear matrix proteins to provide a unique nuclear microenvironment for transcriptional regulation. An LXXLL signature motif is present within the SAP domain of all PIAS proteins. This signature motif has been shown to mediate interactions between nuclear receptors and their co-regulators.<ref>{{cite journal | vauthors = Glass CK, Rosenfeld MG | title = The coregulator exchange in transcriptional functions of nuclear receptors | journal = Genes & Development | volume = 14 | issue = 2 | pages = 121–141 | date = Jan 2000 | pmid = 10652267 | doi = 10.1101/gad.14.2.121 | s2cid = 12793980 | doi-access = free }}</ref> It is also essential for the binding of PIAS3 to androgen receptor. The LXXLL motif represents the minimal requirement for the interaction with the NFκB p65 subunit and for the inhibition of NFκB transcriptional activity.<ref name="Jang_2004" /> It was previously described that the LXXLL motif is also responsible for the retention of PIAS3 in the nucleus.

The Pro-Ile-Asn-Ile-Thr (PINIT) motif represents a highly conserved region of PIAS proteins, which was shown to be involved in the nuclear retention of PIAS3.<ref>{{cite journal | vauthors = Duval D, Duval G, Kedinger C, Poch O, Boeuf H | title = The 'PINIT' motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L | journal = FEBS Letters | volume = 554 | issue = 1–2 | pages = 111–118 | date = Nov 2003 | pmid = 14596924 | doi = 10.1016/s0014-5793(03)01116-5 | s2cid = 23261716 | doi-access = free }}</ref> Within the PINIT domain, the PIAS382-132 region was isolated and characterized as an inhibitory domain that binds and inhibits both the MITF and STAT3 transcription factors.<ref>{{cite journal | vauthors = Levy C, Khaled M, Fisher DE | title = MITF: master regulator of melanocyte development and melanoma oncogene | journal = Trends in Molecular Medicine | volume = 12 | issue = 9 | pages = 406–414 | date = Sep 2006 | pmid = 16899407 | doi = 10.1016/j.molmed.2006.07.008 }}</ref> The RING-finger-like zinc-binding domain (RLD) is one of the most conserved domains of the PIAS family and has been shown to be important for PIAS3 activity as a SUMO-E3 ligase.<ref>{{cite journal | vauthors = Nakagawa K, Yokosawa H | title = PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1 | journal = FEBS Letters | volume = 530 | issue = 1–3 | pages = 204–208 | date = Oct 2002 | pmid = 12387893 | doi = 10.1016/s0014-5793(02)03486-5 | s2cid = 38456991 | doi-access = free }}</ref> The RLD domain is also involved in the positive regulation of SMAD3 by PIAS3.<ref>{{cite journal | vauthors = Long J, Wang G, Matsuura I, He D, Liu F | title = Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 1 | pages = 99–104 | date = Jan 2004 | pmid = 14691252 | pmc = 314145 | doi = 10.1073/pnas.0307598100 | bibcode = 2004PNAS..101...99L | doi-access = free }}</ref>

== Function ==

PIAS3 protein also functions  as a SUMO (small ubiquitin-like modifier)-E3 ligase which catalyzes the covalent attachment of a SUMO protein to specific target substrates. It directly binds to several transcription factors and either blocks or enhances their activity. Alternatively spliced transcript variants of this gene have been identified, but the full-length nature of some of these variants has not been determined.<ref name="entrez" />

== Interactions ==

PIAS3 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[GFI1]],<ref name="Rodel_2000">{{cite journal | vauthors = Rödel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsässer HP, Möröy T | title = The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3 | journal = The EMBO Journal | volume = 19 | issue = 21 | pages = 5845–5855 | date = Nov 2000 | pmid = 11060035 | pmc = 305799 | doi = 10.1093/emboj/19.21.5845 }}</ref> 
* [[HMGA2]]<ref name="Zentner_2001">{{cite journal | vauthors = Zentner MD, Lin HH, Deng HT, Kim KJ, Shih HM, Ann DK | title = Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells | journal = Journal of Biological Chemistry | volume = 276 | issue = 32 | pages = 29805–29814 | date = Aug 2001 | pmid = 11390395 | doi = 10.1074/jbc.M103153200 | s2cid = 33084417 | doi-access = free }}</ref> 
* [[Microphthalmia-associated transcription factor|MITF]],<ref name="Levy_2002" /><ref>{{cite journal | vauthors = Yagil Z, Nechushtan H, Kay G, Yang CM, Kemeny DM, Razin E | title = The enigma of the role of protein inhibitor of activated STAT3 (PIAS3) in the immune response | journal = Trends in Immunology | volume = 31 | issue = 5 | pages = 199–204 | date = May 2010 | pmid = 20181527 | doi = 10.1016/j.it.2010.01.005 }}</ref> 
* [[Mothers against decapentaplegic homolog 2|SMAD2]],<ref name="pmid14691252" />
* [[Mothers against decapentaplegic homolog 3|SMAD3]],<ref name = pmid14691252>{{cite journal | vauthors = Long J, Wang G, Matsuura I, He D, Liu F | title = Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 1 | pages = 99–104 | date = Jan 2004 | pmid = 14691252 | pmc = 314145 | doi = 10.1073/pnas.0307598100 | bibcode = 2004PNAS..101...99L | doi-access = free }}</ref>  and
* [[RELA]].<ref name="Jang_2004" />
{{Div col end}}

== Clinical significance ==
*[[TAR syndrome]]<ref name="Klopocki_2007">{{cite journal | vauthors = Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, König R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S | title = Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome | journal = American Journal of Human Genetics | volume = 80 | issue = 2 | pages = 232–240 | date = Feb 2007 | pmid = 17236129 | pmc = 1785342 | doi = 10.1086/510919 }}</ref>
*[[1q21.1 deletion syndrome]]
*[[1q21.1 duplication syndrome]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K | title = Specific inhibition of Stat3 signal transduction by PIAS3 | journal = Science | location = New York, N.Y. | volume = 278 | issue = 5344 | pages = 1803–1805 | date = Dec 1997 | pmid = 9388184 | doi = 10.1126/science.278.5344.1803 | bibcode = 1997Sci...278.1803C }}
* {{cite journal | vauthors = Rödel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsässer HP, Möröy T | title = The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3 | journal = The EMBO Journal | volume = 19 | issue = 21 | pages = 5845–5855 | date = Nov 2000 | pmid = 11060035 | pmc = 305799 | doi = 10.1093/emboj/19.21.5845 }}
* {{cite journal | vauthors = Junicho A, Matsuda T, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, Fuse H, Muraguchi A | title = Protein inhibitor of activated STAT3 regulates androgen receptor signaling in prostate carcinoma cells | journal = Biochemical and Biophysical Research Communications | volume = 278 | issue = 1 | pages = 9–13 | date = Nov 2000 | pmid = 11071847 | doi = 10.1006/bbrc.2000.3753 }}
* {{cite journal | vauthors = Kotaja N, Aittomäki S, Silvennoinen O, Palvimo JJ, Jänne OA | title = ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation | journal = Molecular Endocrinology | location = Baltimore, Md. | volume = 14 | issue = 12 | pages = 1986–2000 | date = Dec 2000 | pmid = 11117529 | doi = 10.1210/mend.14.12.0569 | s2cid = 32965662 | doi-access = free }}
* {{cite journal | vauthors = Zentner MD, Lin HH, Deng HT, Kim KJ, Shih HM, Ann DK | title = Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 32 | pages = 29805–29814 | date = Aug 2001 | pmid = 11390395 | doi = 10.1074/jbc.M103153200 | s2cid = 33084417 | doi-access = free }}
* {{cite journal | vauthors = Wang LH, Yang XY, Mihalic K, Xiao W, Li D, Farrar WL | title = Activation of estrogen receptor blocks interleukin-6-inducible cell growth of human multiple myeloma involving molecular cross-talk between estrogen receptor and STAT3 mediated by co-regulator PIAS3 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 34 | pages = 31839–31844 | date = Aug 2001 | pmid = 11429412 | doi = 10.1074/jbc.M105185200 | s2cid = 24912586 | doi-access = free }}
* {{cite journal | vauthors = Jiménez-Lara AM, Heine MJ, Gronemeyer H | title = PIAS3 (protein inhibitor of activated STAT-3) modulates the transcriptional activation mediated by the nuclear receptor coactivator TIF2 | journal = FEBS Letters | volume = 526 | issue = 1–3 | pages = 142–146 | date = Aug 2002 | pmid = 12208521 | doi = 10.1016/S0014-5793(02)03154-X | s2cid = 2934712 | doi-access = free }}
* {{cite journal | vauthors = Nakagawa K, Yokosawa H | title = PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1 | journal = FEBS Letters | volume = 530 | issue = 1–3 | pages = 204–208 | date = Oct 2002 | pmid = 12387893 | doi = 10.1016/S0014-5793(02)03486-5 | s2cid = 38456991 | doi-access = free }}
* {{cite journal | vauthors = Yamamoto T, Sato N, Sekine Y, Yumioka T, Imoto S, Junicho A, Fuse H, Matsuda T | title = Molecular interactions between STAT3 and protein inhibitor of activated STAT3, and androgen receptor | journal = Biochemical and Biophysical Research Communications | volume = 306 | issue = 2 | pages = 610–615 | date = Jun 2003 | pmid = 12804609 | doi = 10.1016/S0006-291X(03)01026-X | hdl = 2115/28119 | hdl-access = free }}
* {{cite journal | vauthors = Di Y, Li J, Zhang Y, He X, Lu H, Xu D, Ling J, Huo K, Wan D, Li YY, Gu J | title = HCC-associated protein HCAP1, a variant of GEMIN4, interacts with zinc-finger proteins | journal = Journal of Biochemistry | volume = 133 | issue = 6 | pages = 713–718 | date = Jun 2003 | pmid = 12869526 | doi = 10.1093/jb/mvg091 }}
* {{cite journal | vauthors = Cheng J, Zhang D, Zhou C, Marasco WA | title = Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells | journal = Leukemia Research | volume = 28 | issue = 1 | pages = 71–82 | date = Jan 2004 | pmid = 14630083 | doi = 10.1016/S0145-2126(03)00158-9 }}
* {{cite journal | vauthors = Long J, Wang G, Matsuura I, He D, Liu F | title = Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 1 | pages = 99–104 | date = Jan 2004 | pmid = 14691252 | pmc = 314145 | doi = 10.1073/pnas.0307598100 | bibcode = 2004PNAS..101...99L | doi-access = free }}
* {{cite journal | vauthors = Nojiri S, Joh T, Miura Y, Sakata N, Nomura T, Nakao H, Sobue S, Ohara H, Asai K, Ito M | title = ATBF1 enhances the suppression of STAT3 signaling by interaction with PIAS3 | journal = Biochemical and Biophysical Research Communications | volume = 314 | issue = 1 | pages = 97–103 | date = Jan 2004 | pmid = 14715251 | doi = 10.1016/j.bbrc.2003.12.054 }}
* {{cite journal | vauthors = Wang L, Banerjee S | title = Differential PIAS3 expression in human malignancy | journal = Oncology Reports | volume = 11 | issue = 6 | pages = 1319–1324 | date = Jun 2004 | pmid = 15138572 | doi = 10.3892/or.11.6.1319 }}
* {{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Research | volume = 14 | issue = 7 | pages = 1324–1332 | date = Jul 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }}
{{refend}}

== External links ==
* {{PDBe-KB2|Q9Y6X2|E3 SUMO-protein ligase PIAS3}}

{{JAK-STAT signaling pathway}}